Changes in Disposition of Ezetimibe and Its Active Metabolites Induced by Impaired Hepatic Function: The Influence of Enzyme and Transporter Activities.

Ezetimibe (EZE) is a selective cholesterol absorption inhibitor. Hepatic impairment significantly increases the systemic exposure of EZE and its main active phenolic glucuronide, EZE-Ph. Although changes in efflux transporter activity partly explain the changes in EZE-Ph pharmacokinetics, the causes of the changes to EZE and the effects of the administration route on EZE-Ph remain unclear. A carbon tetrachloride (CCl4)-induced hepatic failure rat model was combined with in vitro experiments to explore altered EZE and EZE-Ph disposition caused by hepatic impairment. The plasma exposure of EZE and EZE-Ph increased by 11.1- and 4.4-fold in CCl4-induced rats following an oral administration of 10 mg/kg EZE, and by 2.1- and 16.4-fold after an intravenous injection. The conversion of EZE to EZE-Ph decreased concentration-dependently in CCl4-induced rat liver S9 fractions, but no change was observed in the intestinal metabolism. EZE-Ph was a substrate for multiple efflux and uptake transporters, unlike EZE. In contrast to efflux transporters, no difference was seen in the hepatic uptake of EZE-Ph between control and CCl4-induced rats. However, bile acids that accumulated due to liver injury inhibited the uptake of EZE-Ph by organic anion transporting polypeptides (OATPs) (glycochenodeoxycholic acid and taurochenodeoxycholic acid had IC50 values of 15.1 and 7.94 µM in OATP1B3-overexpressed cells). In conclusion, the increased plasma exposure of the parent drug EZE during hepatic dysfunction was attributed to decreased hepatic glucuronide conjugation, whereas the increased exposure of the metabolite EZE-Ph was mainly related to transporter activity, particularly the inhibitory effects of bile acids on OATPs after oral administration.

Therapeutic Effect of Continuous Blood Purification Combined with Humanized Nursing in Patients with Severe Sepsis.

This work aimed to explore the effect of humanized nursing on the patients' recovery from severe sepsis based on continuous blood purification (CBP). 90 patients with severe sepsis were randomly and equally divided into a control group (basic intensive nursing + CBP) and a therapy group (humanized nursing + CBP). Before treatment and on the 7th and 14th days after treatment, indicators of patients were compared, including white blood cell (WBC), tumor necrosis factor (TNF-α), hepatic and renal function, C-reactive protein (CRP), brain natriuretic peptide (BNP), procalcitonin (PCT), and erythrocyte sedimentation rate (ESR). The mortality and nursing satisfaction were compared. After treatment, the saturation of pulse oxygen (SPO2) in the therapy group (85 ± 20 and 91 ± 9) was higher than that in the control group (78 ± 28 and 82 ± 18, respectively), and the lactic acid level (LAL) was greatly lower (2.8 ± 2.4 and 1.6 ± 0.9 vs. 4.3 ± 2.3 and 2.3 ± 2.7). The Acute Physiology and Chronic Health Evaluation II (APACHE-II) score after treatment was lower (13.67 ± 4.28 and 8.45 ± 5.12 vs. 17.34 ± 6.4 and 11.46 ± 4.23). The BNP, blood urea nitrogen (BUN), and CRP levels were decreased, and so did inflammatory indicators. The survival rate reached 71% and 47% in the therapy group and control group, respectively; and the nursing satisfaction was 97.80% and 26.67%, respectively. Humanized nursing combined with CBP could improve the therapeutic effect and speed up the recovery from severe sepsis.

Mechanistic Study on the Effect of Renal Impairment on the Pharmacokinetics of Vildagliptin and its Carboxylic Acid Metabolite.

PURPOSE: To clarify the mechanism of renal impairment leading to different degrees of increased plasma exposure to dipeptidyl peptidase 4 inhibitor vildagliptin and its major metabolite, M20.7. METHODS: The 5/6 nephrectomized (5/6 Nx) rat model, to simulate chronic renal failure (CRF) patients, combined with kidney slices and transporter studies in vitro were used to assess this pharmacokinetic differences. RESULTS: After intragastric administration to 5/6 Nx rats, vildagliptin showed increased plasma levels by 45.8%, and M20.7 by 7.51 times, which was similar to patients with severe renal impairment. The recovery rate of M20.7 in urine and feces increased by less than 20%, showing limited effect of renal impairment on vildagliptin metabolism. In vitro studies found M20.7 to be the substrate for organic anion transporter 3 (OAT3). However, the active uptake of M20.7 in renal slices showed no difference between the 5/6 Nx and normal rats. In OAT3 overexpressed cells, the protein-bound uremic toxins, 3-carboxy-4-methyl-5propyl-2-furanpropionate (CMPF), hippuric acid (HA) and indoxyl sulfate (IS), which accumulate in CRF patients, inhibited M20.7 uptake with IC50 values of 5.75, 29.0 and 69.5 µM respectively, far lower than plasma concentrations in CRF patients, and showed a mixed inhibition type. CONCLUSIONS: The large increase in plasma exposure of M20.7 could be attributed to the accumulation of uremic toxins in CRF patients, which inhibited OAT3 activity and blocked renal excretion of M20.7, while vildagliptin, with high permeability, showed a slight increase in plasma exposure due to reduced glomerular filtration.